title: Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTc modelling in a phase 1 study with oral rac-sotalol.
abstract: OBJECTIVE
  To study the differences in QTc interval on ECG in response to a single oral dose of rac-sotalol in men and women.
  
  
  METHODS
  Continuous 12-lead ECGs were recorded in 28 men and 11 women on a separate baseline day and following a single oral dose of 160 mg rac-sotalol on the following day. ECGs were extracted at prespecified time points and upsampled to 1000 Hz and analyzed manually in a central ECG laboratory on the superimposed median beat. Concentration-QTc analyses were performed using a linear mixed effects model.
  
  
  RESULTS
  Rac-sotalol produced a significant reduction in heart rate in men and in women. An individual correction method (QTc I) most effectively removed the heart rate dependency of the QTc interval. Mean QTc I was 10 to 15 ms longer in women at all time points on the baseline day. Rac-sotalol significantly prolonged QTc I in both genders. The largest mean change in QTc I (ΔQTc I) was greater in females (68 ms (95% confidence interval (CI) 59, 76 ms) vs. 27 ms (95% CI 22, 32 ms) in males). Peak rac-sotalol plasma concentration was higher in women than in men (mean Cmax 1.8 μg ml(-1) (range 1.1-2.8) vs. 1.4 μg ml(-1) (range 0.9-1.9), P = 0.0009). The slope of the concentration-ΔQTc I relationship was steeper in women (30 ms per μg ml(-1) vs. 23 ms per μg ml(-1) in men; P = 0.0135).
  
  
  CONCLUSIONS
  The study provides evidence for a greater intrinsic sensitivity to rac-sotalol in women than in men for drug-induced delay in cardiac repolarization.
authors.affiliation: Karolinska Institute, Department of Clinical Sciences, Danderyd's Hospital, Division of Cardiovascular Medicine, Stockholm, Sweden.
authors.forename: Borje
authors.initials: B
authors.lastname: Darpo
authors.forename: Dilip R
authors.initials: DR
authors.lastname: Karnad
authors.forename: Fabio
authors.initials: F
authors.lastname: Badilini
authors.forename: Jeff
authors.initials: J
authors.lastname: Florian
authors.forename: Christine E
authors.initials: CE
authors.lastname: Garnett
authors.forename: Snehal
authors.initials: S
authors.lastname: Kothari
authors.forename: Gopi Krishna
authors.initials: GK
authors.lastname: Panicker
authors.forename: Nenad
authors.initials: N
authors.lastname: Sarapa
mesh_terms: D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D004562:Electrocardiography; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D016014:Linear Models; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D008297:Male; D018570:Risk Assessment; D012307:Risk Factors; D012737:Sex Factors; D013015:Sotalol / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics
chemical_list: D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D013015:Sotalol
keywords: PK/PD; QT prolongation; QT/QTc; gender; gender difference; rac-sotalol